A couple of things that I will be looking for prior to reading them is whether Farkas's is the author. There are rumors that he is not. Second thing to look for is if the new docs address Sarepta's addendum only or if they re-analyze the entire eteplirsen package and remove some of their previous comparative analysis like Becker's, exon 45 as an acceptable negative control replacement for Sarepta's match historical cohort and percent of normal dystrophin levels. I believe the criticism of the original BD's has altered the landscape at the Neurological Peripheral Committee. Lastly, the "standard". There has been much discussion on this topic and the statute is at odds with this committee's interpretation of said statute. Look for a more nuanced committee interpretation of FDASIA and followup AA statute standard. This is where the Congressional letters and attendance at the Adcom will have an effect.
Anyone who compares the exon 51 pathogenesis to the exon 45 or a much milder form of DMD, like Becker's in his stat. analysis is significantly uninformed. His belief that a control cohort for exon 51 should contain an amalgam of different exons including Beckers patients is incompetent. I could go on.
simp, Remember, Adam F. has a really bad track record. So bad that I would correct his analysis and bring up some of his predictions. Result, He banned me from his website. He told me my analysis was "boring". This is a nonintellectually curious individual. There are others in the field of biotech financial journalism that are not only curious but honest.
I would be against political lobbying the FDA if the FDA wasn't political, but it is political.The only pressure that the FDA will bow to are purse strings and sun light. The Farkas committee has been exposed as an uninformed, intellectually non curious bureaucrats. To be fair to the FDA all their committees have applied Accelerated Approval statutes and the FDA's guidelines properly except Farkas's committee. I believe the FDA hierarchy has spoken with Farkas and his putative analysis and we will see a much favorable Addendum response from this committee. If Farkas dismisses the FDA's influence a Civil War will erupt outside the Adcom and for days and weeks to come. The subsequent "sunshine" from this committee will result in congressional hearings and changes to the FDASIA/AA law. The FDA does not want this to happen. My guess a 10-3 vote for efficacy and an even higher vote for risk/benefit.
Acadia's briefing docs for Niplazid pre-Adcom contained the following risk-benefit statement, "benefit, however small, outweighs zero-risk, and even a small benefit in a disabling disease is valuable". What a novel conclusion. Query, Aren't eteplirsen treated patient clinical measure scores after 4 years of treatment vs. matched historical control provide at least a "small benefit"? Zero safety concerns.
Zaire Sahenk MD, PhD's dystrophin presentation to FDA. Outstanding job that corrects most of the FDA's misunderstanding of dystrophin qualification/quantification and explains that the AxioVision software used for IMF visualizations highlights negative fibers and NOT for positive fibers. This was another ridiculous assertion that Farkas advanced in his paper. Link on twitter
On DMD, eteplirsen and outdated FDA
Farkas's use of "percent of normal" dystrophin is illustrative of his ignorance of the DMD pathology. This phrase suggests or implies that 100% of dystrophin in healthy males is the target or goal and that a result of only 1% should be viewed in this context. This is not only a ridiculous comparison but really exposes their lack of curiosity in the field of DMD research, dystrophin levels of exon 51 boys and pride in their own professional ethic in discharging their responsibilities as FDA drug development guardians. Farkas might not be embarrassed by his work product but I'm embarrassed for him.
Dennis, I'm aware of the general purpose of briefing docs but I challenge anyone who have read the eteplirsen docs to make the case that what they read was a focusing mechanism prepared by Farkas. When Farkas discredits the matched historical controls the FDA sanctioned and replaces them with the Drisapersen control in their analysis how can he claim that only placebo controlled cohorts enrolled within a treatment trial is the only acceptable comparison population? How is it a focusing mechanism when he flippantly compares eteplirsen induced dystrophin levels for exon 51 DMD to Becker's? I have a prediction for you. I believe the FDA was embarrassed by the documents released by Farkas and there have been internal discussions with this putative analysis and the next round of BD's will be much more in-line with current research in this area and will contain accurate comparative analysis. Sarepta's Addendum was the focusing mechanism that Farkas must address and everyone is watching.
Dono, I completely agree with your previous post. I'm attempting to inform those interested in this topic. I have recently emailed Ron Farkas and I will update this post if and when he responds.
How can the FDA now claim that the efficacy standard of "substantial evidence" for AA is consistent with the FDA's own words, "A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit". This is worth repeating, "but is not itself a measure of clinical benefit"!!!!!!!!!!!!!!!!!!!!
Sorry for beating the same drum but here's the latest from the FDA on AA..."The FDA instituted its Accelerated Approval Program to allow for earlier approval of drugs that treat serious conditions, and that fill an unmet medical need based on a surrogate endpoint. A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval.
Drug companies are still required to conduct studies to confirm the anticipated clinical benefit. These studies are known as phase 4 confirmatory trials. If the confirmatory trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug. If the confirmatory trial does not show that the drug provides clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.
Posters that express the opinion that the "standard of efficacy" is still "substantial proof" are extracting that standard from the original Orphan Drug Act. Farkas brought this up in the briefing docs and JMP used the same standard. The Accelerated Approval law of 2013, passed by both houses of Congress and signed into law by Obama, clearly "broadens" the efficacy standard. "Broadens" is the exact word the FDA uses to describe the new standard. If your position is that the FDA is reluctant to change the "new" standard from "substantial" to "may lead to a clinical benefit" then I agree with you. Congress writes the laws, President signs the laws and Agencies administer the laws. The FDA does not want to surrender this power. Read the 2013 AA law, read the FDA's own guidance for the drug development industry and they quote the new law. The only people citing the old standard for AA is you, Farkas, JMP and other misinformed investors. I'm cognizant of the FDA's and Farkas's motives for not applying the new standard but what is your's?
Sentiment: Strong Buy